early phase human drug trial to investigate dynamin 101 (dyn101) in patients ≥ 16 years with centronuclear myopathies

Conditions: Centronuclear Myopathy

Summary: there are no available treatments aside from supportive care for patients with centronuclear myopathy (cnm). this trial will assess the safety, tolerability, pharmacokinetics (pk) and pharmacodynamics (pd)/preliminary efficacy of a new medicine called dyn101 in patients ≥ 16 years of age with cnm caused by mutations in dynamin2 (dnm2) or myotubularin1 (mtm1). the trial will consist of a consent, a screening period, a run-in period (if applicable), a single dose treatment part (sad) with 4 weeks of follow-up after the drug administration and a washout period of at least 12 weeks (followed by follow-up phone calls), a multiple dose treatment part (mad) of 12 weeks of weekly dosing, and a multiple dose extension part of 12 weeks. all subjects will participate in the sad, mad, and mad extension parts, unless they withdraw. during this time, multiple test will be performed in order to better understand how the drug is distributed and then later removed from the body and whether there any signs of an effect. as this trial is investigational, there is no defined, expected benefit for subjects who participate in this trial except a better knowledge of their disease.

there are currently no available treatments aside from supportive care for patients with centronuclear myopathy (cnm). this trial will assess the safety, tolerability, pk and pd/preliminary efficacy of dyn101 in patients ≥ 16 years of age with cnm caused by mutations in dnm2 or mtm1. dyn101 is a synthetically manufactured constrained ethyl gapmer antisense oligonucleotide (aso) directed against dnm2 pre-messenger ribonucleic acid (mrna). dyn101 will be provided as a sterile concentrated solution for reconstitution into an infusion solution for intravenous (iv) administration, and will be diluted into a 0.9% sodium chloride solution before administration. the trial will consist of a pre-screening consent, a screening period, a run-in period (if applicable), a sad part with 4 weeks of follow-up after investigational medicinal product (imp) administration and a washout period of at least 12 weeks (followed by follow-up phone calls until the mad part starts), a mad part of 12 weeks, and a mad extension part of 12 weeks. all subjects will participate in the sad, mad, and mad extension parts, unless they withdraw. end-of-treatment assessments will be performed after 24 weeks of mad treatment have been completed, i.e. at the week 25 visit. subjects will be followed up on adverse events (aes) and concomitant medications 3 months after the last imp administration. an interim analysis will be performed when all subjects in cohort 1 and 2 have completed 12 weeks of mad treatment. the primary analysis will be performed when all subjects in all cohorts have completed 12 weeks of mad treatment or discontinued earlier. the final analysis will be performed when all subjects have completed 24 weeks of mad treatment (12 weeks in the mad part + 12 weeks in the mad extension part; week 25 visit) or discontinued earlier. as this trial is investigational, there is no defined, expected benefit for subjects who participate in this trial except a better knowledge of their pathology, and the knowledge that they contribute to rna-targeted therapy for cnm patients carrying mtm1 and dnm2 mutations.

Eligibility criteria:
inclusion criteria: 1. male or female aged ≥ 16 years on the date of signing the main informed consent form (icf). 2. have a documented mutation in dnm2 or mtm1. 3. have a symptomatic cnm in the opinion of the investigator, at least mild to moderately affected, i.e. showing clinical symptoms in at least 2 of the relevant 4 domains that will be investigated in this trial (respiratory, muscle strength, muscle function, and dysphagia), and be ambulatory, i.e. being able to walk 10 steps, if needed with support/assisted. if a subject is non-ambulatory but highly functioning in the view of the investigator, he/she may be included following discussion with the sponsor. 5. have an understanding, ability, and willingness to fully comply with visit frequency, trial procedures and restrictions, including contraceptive requirements. 6. able to provide written, signed and dated informed consent/assent to participate in the trial. parental consent (one or both parents) and an assent for subjects \< 18 years may be required per local legislation. exclusion criteria: 1. clinically significant liver disease. 2. clinically significant renal disease. 3. presence of significant co-morbidities or conditions other than cnm or clinically significant (cs) findings during screening of medical history, physical examination, laboratory testing, vital signs or ecg recording for which, in the opinion of the investigator and the medical monitor, participation would not be in the best interest of the subject (e.g. compromise the safety or well-being) or that could prevent, limit, or confound the protocol-specified assessments (e.g. taking a muscle biopsy). 4. for female subjects of child-bearing potential: pregnant or breastfeeding, or planning to become pregnant during the trial. 5. current or past abuse of alcohol or recreational/narcotic drugs (with the exception of caffeine and nicotine), which in the investigator's opinion would compromise the subject's safety and/or compliance with the trial procedures. 6. currently enrolled in any interventional trial or scheduled to participate in such a trial whilst participating in this trial. subjects are allowed to participate in registry studies. 7. current or relevant history of physical or psychiatric illness, any medical disorder that may require treatment or make the subject unlikely to fully complete the trial, or any condition that presents undue risk from the imp or procedures. 8. intake of any disallowed therapies as noted in section 5.5 within 12 weeks before the planned first imp administration. 9. known or suspected intolerance or hypersensitivity to imp ingredients or closely-related compounds, or history of a significant allergic reaction to imp ingredients as determined by the investigator, such as anaphylaxis requiring hospitalization. 10. legally incapacitated or have limited legal capacity. lack of mental capacity to fully understand the protocol requirements and complete all study required procedures. note: retesting of subjects should always be discussed with the sponsor and/or medical monitor. retesting of laboratory values that lead to exclusion will be allowed once using an unscheduled visit during the screening period to assess eligibility. this visit should be at least 2 weeks later than the original screening visit.